HIV infection in United States and several other developed countries is now largely driven by drug abusing populations. Since both HIV and drugs of abuse independently cause injury to the brain, researchers face multiple challenges in the design of studies to address the pathogenesis or develop effective therapies. This is further complicated by the fact that these patients often abuse multiple drugs and have other co-morbidities. Nonetheless, it is clear that the use of antiretroviral drugs alone is not sufficient and neuroprotective strategies need to be used in these patient populations. Yet no clinical trials have been conducted to date in this patient population. On the contrary, drug abusers have been excluded from most clinical trials on HIV dementia. While the research community recognizes the importance of studying the combined effects of these substances challenges faced include the large number of variables that need to be considered and the lack of ideal small animal models to study these combined effects. Despite these drawbacks, we rationalize that information available to date clearly suggests that there are common subcellular mechanisms involved in neural injury by HIV proteins and drugs of abuse, which can be exploited to develop novel therapeutic approaches for this patient population. HIV proteins and select drugs of abuse may contribute to the pathogenesis of HIVD through non-mutually exclusive mechanisms including 1) direct neurotoxicity, 2) glial activation, and 3) increased viral replication. We recently screened over 2000 compounds that have been approved by the Federal Drug Administration for human use and found that two compounds within the class of the selective serotinergic release inhibitors (SSRI), fluoxetine and paroxetine, have potent neuroprotective effects against the combined effects of drugs of abuse and HIV proteins. Interestingly, in a recent retrospective clinical study it was found that HIV patients on antidepressants had better neurocognitive function and lower CSF viral loads (Letendre et al, 2007). In another study with magnetic resonance spectroscopy, HIV infected patients on SSRIs had higher levels of N-acetyl aspartate suggestive of neuroprotection (Linda Chang, University of Hawaii, personal communication). For these reasons, we have designed an experimental study to determine if fluoxetine and paroxetine can impact the combined effects of HIV and drugs of abuse in various cell types in the brain and determine the mechanisms by which such neuroprotection may occur. Another novel aspect of our study is that we will study the combined effects of opiates and cocaine, since they are commonly used together. Thus this study will provide critical information needed to design future clinical trials with these agents for HIV infected drug abusers. We propose three specific aims. (1). Determine if SSRI can modulate the effect of HIV proteins and drugs of abuse on neuronal function (2) Determine if SSRI can modulate effects of HIV proteins and drugs of abuse on glial cell function (3) Determine if SSRI can modulate the effect of HIV proteins and drugs of abuse on neural progenitor cell function. PUBLIC HEALTH RELEVANCE Currently, there is no available neuroprotective therapy for HIV infected drug abusers who may be afflicted by a dementing illness. We have screened over 2,00 compounds and identified a class of antidepressant compounds that have novel brain protective properties. We will explore their mechanism of action and conduct other preclinical studies that are needed to take them to clinical trials.